Morpholine derivatives as dopamine receptor subtype ligands

ABSTRACT

A class of substituted morpholine derivatives of formula ##STR1## wherein Y represents an optionally substituted bicyclic heteroaromatic ring system containing one or two nitrogen atoms, the ring system comprising a six-membered aromatic or heteroaromatic ring fused to a five- or six-membered heteroaromatic ring; and Z represents an optionally substituted arylalkyl, aryloxymethyl or arylalkoxymethyl group, are ligands for dopamine receptor subtypes within the body and are therefore useful in the treatment and/or prevention of disorders of the dopamine system, in particular schizophrenia.

This application is a 371 of PCT/GB94/02557 filed Nov. 21, 1994.

This invention relates to a particular class of morpholine derivativeswhich are ligands for dopamine receptor subtypes within the body and aretherefore of use in the treatment and/or prevention of disorders of thedopamine system, including schizophrenia, depression, nausea,Parkinson's disease, tardive dyskinesias and extrapyramidal side-effectsassociated with treatment by conventional neuroleptic agents,neuroleptic malignant syndrome, and disorders of hypothalamic-pituitaryfunction such as hyperprolactinaemia and amenorrhoea.

Upper gastrointestinal tract motility is believed to be under thecontrol of the dopamine system. The compounds according to the presentinvention may thus be of use in the prevention and/or treatment ofgastrointestinal disorders, and the facilitation of gastric emptying.

Dependence-inducing agents such as cocaine and amphetamine have beenshown to interact with the dopamine system. Compounds capable ofcounteracting this effect, including the compounds in accordance withthe present invention, may accordingly be of value in the prevention orreduction of dependence on a dependence-inducing agent.

Dopamine is known to be a peripheral vasodilator; for example, it hasbeen shown to exert a dilatory effect on the renal vascular bed. Thisimplies that the compounds of the present invention may be beneficial incontrolling vascular blood flow.

The localisation of dopamine receptor mRNA in rat heart and largevessels has been noted. This suggests a role for dopamine receptorligands in controlling cardiovascular function, either by affectingcardiac and smooth muscle contractility or by modulating the secretionof vasoactive substances. The compounds according to the presentinvention may thereforel be of assistance in the prevention and/ortreatment of such conditions as hypertension and congestive heartfailure.

Molecular biological techniques have revealed the existence of severalsubtypes of the dopamine receptor. The dopamine D₁ receptor subtype hasbeen shown to occur in at least two discrete forms. Two forms of the D₂receptor subtype, and at least one form of the D₃ receptor subtype, havealso been discovered. More recently, the D₄ (Van Tol et al., Nature(London), 1991, 350, 610) and D₅ (Sunahara et al., Nature (London),1991, 350, 614) receptor subtypes have been described.

The compounds in accordance with the present invention, being ligandsfor dopamine receptor subtypes within the body, are accordingly of usein the treatment and/or prevention of disorders of the dopamine system.

The present invention accordingly provides a compound of formula I, or asalt thereof or a prodrug thereof: ##STR2## wherein Y represents anoptionally substituted bicyclic heteroaromatic ring system containingone or two nitrogen atoms, the ring system comprising a six-memberedaromatic or heteroaromatic ring fused to a five- or six-memberedheteroaromatic ring; and

Z represents an optionally substituted aryl(C₁₋₆)alkyl, aryloxymethyl oraryl(C₁₋₆)alkoxymethyl group.

The bicyclic heteroaromatic ring system Y in formula I above comprises aphenyl or pyridyl moiety fused at any position to a pyrrolyl or pyridylmoiety; or a phenyl moiety fused at any position to a pyrazolyl,imidazolyl, pyrazinyl, pyrimidinyl or pyridazinyl moiety. Suitably, thering system Y comprises a phenyl or pyridyl moiety fused at any positionto a pyrrolyl, pyridyl or imidazolyl moiety. More particularly, Y mayrepresent an optionally substituted 2- or 3-indolyl, 2- or 3-quinolyl,3-indazolyl, 2-benzimidazolyl, or 2- or 3-pyrrolo[2,3-b]pyridyl ringsystem.

The aryl moiety of the substituent Z in formula I above is suitably anoptionally substituted phenyl or naphthyl group.

As used herein, the expression "C₁₋₆ alkyl", and derived expressionssuch as "C₁₋₆ alkoxy", refers to straight-chained and branched groupscontaining from 1 to 6 carbon atoms. Typical examples of alkyl groupsinclude methyl and ethyl groups, and straight-chained or branched propyland butyl groups. Particular alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl and t-butyl.

The groups Y and Z as defined above may each be unsubstituted, orindependently substituted by one or more, preferably up to three,optional substituents. Examples of suitable substituents on the groups Yand Z include halogen, trifluoromethyl, cyano, nitro, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy,aryl(C₁₋₆)alkoxy and C₂₋₆ alkylcarbonyl.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine, especially chlorine.

Particular values for the group Z as defined above include benzyl,phenethyl, phenoxymethyl, chlorophenoxymethyl, methoxy-phenoxymethyl andbenzyloxymethyl.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoicacid, oxalic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g. sodium or potassium salts; alkalineearth metal salts, e.g. calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g. quaternary ammonium salts.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention have at least one asymmetriccentre, and they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof are encompassedwithin the scope of the present invention.

A particular sub-class of compounds according to the invention isrepresented by the compounds of formula IIA, and salts and prodrugsthereof: ##STR3## wherein n is zero, 1 or 2;

one of V and X is CH or nitrogen and the other is CH;

W represents a chemical bond or an oxygen atom;

R¹ represents hydrogen or C₁₋₆ alkyl; and

R² and R³ independently represent hydrogen, halogen, trifluoromethyl,cyano, nitro, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkyl,C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy or C₂₋₆ alkylcarbonyl.

Suitably, one of V and X represents nitrogen and the other is CH.

Suitably, R¹ is hydrogen.

Suitable values of R² include hydrogen, methyl, ethyl, isopropyl,methoxy, benzyloxy, fluoro and chloro, especially hydrogen.

Suitably, R³ represents hydrogen, chloro or methoxy, especially chloro.

Another sub-class of compounds according to the invention is representedby the compounds of formula IIB, and salts and prodrugs thereof:##STR4## wherein n, W, R¹, R² and R³ are as defined with reference toformula IIA above; and

U represents nitrogen or CH.

A further sub-class of compounds according to the invention isrepresented by the compounds of formula IIC, and salts and prodrugsthereof: ##STR5## wherein n, W, R² and R³ are as defined with referenceto formula IIA above.

Specific compounds within the scope of the present invention include:

3-(2-benzylmorpholin-4-ylmethyl)indole;

3-(2-phenoxymethylmorpholin-4-ylmethyl)indole;

3-[2-(2-phenylethyl)morpholin-4-ylmethyl]indole;

3-(2-phenoxymethylmorpholin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;

3-[2-(2-phenylethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;

2-(2-phenoxymethylmorpholin-4-ylmethyl)benzimidazole;

2-[2-(2-phenylethyl)morpholin-4-ylmethyl)benzimidazole;

3-[2-(4-chlorophenoxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;

2-[2-(4-chlorophenoxymethyl)morpholin-4-ylmethyl]benzimidazole;

3-(2-phenoxymethylmorpholin-4-ylmethyl)quinoline;

3-[2(S)-(benzyloxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;

3-[2(R)-(benzyloxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;

3-[2-(4-methoxyphenoxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;

3-[2-(3-chlorophenoxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the compositions may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

In the treatment of schizophrenia, a suitable dosage level is about 0.01to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The compounds in accordance with the present invention may be preparedby a process which comprises reacting a compound of formula III with acompound of formula IV: ##STR6## wherein Y and Z are as defined above,and L represents a suitable leaving group.

The leaving group L is suitably a halogen atom, e.g. chloro; or adialkylamino group, e.g. dimethylamino.

When L represents a halogen atom, the reaction between compounds III andIV is conveniently carried out by stirring the reactants at an elevatedtemperature under basic conditions in a suitable solvent, for examplepotassium carbonate in ethanol at a temperature in the region of 80° C.Where L represents a dialkylamino group, the reaction is convenientlyeffected by heating the reactants in an inert solvent such as toluene,typically at the reflux temperature of the solvent.

In an alternative procedure, the compounds according to the inventionwherein Y represents an optionally substituted indol-3-yl, indazol-3-ylor 4-, 5-, 6- or 7-azaindol-3-yl moiety may be prepared by reacting acompound of formula IV as defined above with a compound of formula V:

    Y.sup.1 --H                                                (V)

wherein Y¹ represents an optionally substituted indol-3-yl, indazol-3-ylor 4-, 5-, 6- or 7-azaindol-3-yl moiety; in the presence of asubstantially equimolar amount of formaldehyde.

The reaction is conveniently carried out by stirring the reactants atambient temperature in aqueous acetic acid, optionally in the presenceof a buffer such as sodium acetate trihydrate.

The formaldehyde may be utilised in the form of paraformaldehyde; or asa solution of formaldehyde in an inert solvent, e.g. 38% aqueousformaldehyde.

In a further procedure, the compounds according to the invention whereinY represents an optionally substituted 3-quinolyl moiety may be preparedby reacting a compound of formula IV as defined above with a compound offormula VI:

    Y.sup.2 --CHO                                              (VI)

wherein Y² represents an optionally substituted 3-quinolyl moiety; inthe presence of anhydrous formic acid.

The reaction is conveniently effected by stirring the reactants at anelevated temperature, typically a temperature in the region of 120° C.This is an example of the Leuckart-Wallach reaction, which is describedin more detail in Org. React., 1949, 5, 301.

The intermediates of formula IV may conveniently be prepared by reactingethanolamine-O-sulphate with the appropriate epoxide of formula VII:##STR7## wherein Z is as defined above; as described in J. Pharm.Pharmacol., 1990, 42, 797.

The reaction is suitably effected by stirring the reactants with sodiumhydroxide in aqueous methanol at a temperature in the region of 40° C.;followed by treating the reaction mixture with solid sodiun hydroxideand heating in toluene to approximately 65° C.

Where they are not commercially available, the starting materials offormula III, V, VI and VII may be prepared by procedures analogous tothose described in the accompanying Examples, or by standard methodswell known from the art.

It will be appreciated that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further desired compound of formula I using techniquesknown from the art.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds useful in this invention potently inhibit [³ H]-spiperonebinding to human dopamine D₄ receptor subtypes expressed in clonal celllines.

[³ H]-Spiperone Binding Studies

Clonal cell lines expressing the human dopamine D₄ receptor subtype wereharvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffercontaining 5 mM MgSO₄ for 20 min on ice. Membranes were centrifuged at50,000 g for 15 min at 4° C. and the resulting pellets resuspended inassay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM EDTA, 1.5 mM CaCl₂,5 mM MgCl₂, 5 mM KCl, 120 mM NaCl, and 0.1% ascorbic acid) at 20 mg/mlwet weight. Incubations were carried out for 60 min at room temperature(22° C.) in the presence of 0.05-2 nM [³ H]-spiperone or 0.2 nM fordisplacement studies and were initiated by addition of 20-100 μg proteinin a final assay volume of 0.5 ml. The incubation was terminated byrapid filtration over GF/B filters presoaked in 0.3% PEI and washed with10 ml ice-cold 50 mM Tris-HCl, pH 7.4. Specific binding was determinedby 10 μM apomorphine and radioactivity determined by counting in a LKBbeta counter. Binding parameters were determined by non-linear leastsquares regression analysis, from which the inhibition constant K_(i)could be calculated for each test compound.

The compounds of the accompanying Examples were tested in the aboveassay, and all were found to possess a K_(i) value for displacement of[³ H]-spiperone from the human dopamine D₄ receptor subtype of below 1.5μM.

EXAMPLE 1 3-((2(RS)-(Phenylmethyl)morpholin-4-yl)methyl)-indole HydrogenOxalate

3-(Dimethylaminomethyl)indole (688 mg, 3.9 mmol) and2(RS)-(phenylmethyl)morpholine (700 mg, 3.9 mmol, J. Pharm. Pharmacol.1990, 42, 797-799), were heated at reflux in toluene (20 ml), withstirring, for 16 hours. The reaction mixture was cooled, evaporated todryness and the crude product was purified by column chromatography onsilica using ethyl acetate/methanol (9:1) to afford the title productfree base as a beige gum (1.10 g, 92%). The hydrogen oxalate salt had mp122°-124° C. (ethanol). ¹ H NMR (360 MHz, D₂ O) δ2.84 (2H, d, J=6 Hz),2.96 (1H, dd, J₁ =J₂ =12 Hz), 3.16 (1H, ddd, J₁ =4, J₂ =J₃ =12 Hz),3.40-3.47 (2H, m), 3.74 (1H, dd, J₁ =J₂ =12 Hz), 3.97-4.10 (2H, m), 4.51(1H, d, J=14Hz), 4.58 (1H, d, J=14 Hz), 7.20-7.36 (7H, m), 7.55-7.58(2H, m), 7.71 (1H, d, J=7 Hz). Found: C, 66.31; H, 6.01; N, 7.01. C₂₀H₂₂ N₂ O. C₂ H₂ O₄ requires C, 66.65; H, 6.10; N, 7.07%.

EXAMPLE 2 3-((2(RS)-(Phenoxymethhyl)morpholin-4-yl)methyl)-indoleHydrogen Oxalate

Step A: 2(RS)-(Phenoxymethyl)morpholine

2-Aminoethyl hydrogen sulphate (49 g, 0.347 mol) was added in portionsto a mixture of (±)-1,2-epoxy-3-phenoxypropane (11.2 ml, 0.083 mol),sodium hydroxide (26.4 g, 0.66 mol) in water (50 ml) and methanol (20ml). After addition the reaction mixture was stirred at 40° C. (oil bathtemperature) for 2 hours. The reaction mixture was cooled, sodiumhydroxide pellets (20.65 g, 0.516 mol) and toluene (80 ml) were added,then the reaction mixture stirred, whilst heating at 65° C. (oil bathtemperature) for 7.5 hours. The reaction mixture was cooled, toluene (40ml) and water (140 ml) were added. The toluene phase was extracted with2M hydrochloric acid (2×60 ml). The acid extracts were combined, 40%sodium hydroxide solution added to pH=11, then extracted with toluene(2×60 ml). The combined organics were dried (sodium sulphate) thenevaporated to give a colourless gum (10 g) which was purified by columnchromatography on silica, using neat ethyl acetate to remove thelipophilic impurities then ethyl acetate/methanol/ammonia (9:1:0.1) toelute the required product as a colourless oil (7.0 g, 44%). Rf 0.22 indichloromethane/methanol (9:1) on silica plates MS CI⁺, m/z=194 for(M+H)⁺. ¹ H NMR (360 MHz, CDCl₃) δ2.54-2.85 (2H, m), 2.92 (1H, ddd, J₁=2, J₂ =J₃ =12 Hz), 3.05 (1H, dd, J₁ =2, J₂ =12 Hz), 3.67 (1H, ddd, J₁=2, J₂ =J3=12 Hz), 3.83-4.03 (4H, m), 6.88-6.97 (3H, m), 7.23-7.30 (2H,m).

Step B: 3-((2(RS)-(Phenoxymethyl)morpholin-4-yl)methyl)-indole HydrogenOxalate

3-(Dimethylaminomethyl)indole (688 mg, 3.9 mmol) and2(RS)-(phenoxymethyl)morpholine (754 mg, 3.9 mmol) were heated at refluxin toluene (20 ml), with stirring, for 5 hours. The reaction mixture wascooled, treated with silica (200 mg) and activated charcoal (200 mg),then filtered and evaporated to afford the title compound free base(1.15 g, 91%) as a gum. The hydrogen oxalate salt had m.p 169°-°171° C.(ethanol/acetone). ¹ H NMR (360 MHz, DMSO-d₆) δ2.40-2.60 (1H, m), 3.01(1H, d, J=12 Hz), 3.17 (1H, d, J=12 Hz), 3.62 (1H, dd, J₁ =J₂ =12 Hz),3.90-4.05 (7H, m), 6.88-7.41 (9H, m), 7.70 (1H, d, J=8 Hz), 11.19 (1H,broad s). Found: C, 66.94; H, 6.15; N, 7.12. C₂₀ H₂₂ N₂ O₂. 0.7C₂ H₂ O₄requires C, 66.69; H, 6.12; N, 7.27%.

EXAMPLE 3 3-((2(RS)-(2-Phenylethyl)morpholin-4-yl)methyl)-indoleHydrogen Oxalate

Step A: (+)-(3,4-Epoxybutyl)-benzene

Dimethyl sulphoxide (100 ml) was added over 5 minutes to sodium hydride(6.76 g of a 55% oil dispersion, 0.155 mol) under a nitrogen atmosphere.The mixture was stirred vigorously for 10 minutes, then diluted withanhydrous tetrahydrofuran (80 ml). The mixture was cooled to 5° C. and asolution of trimethylsulphonium iodide (31.63 g, 0.155 mol) in dimethylsulphoxide (80 ml) was added slowly keeping the temperature of thereaction mixture at 5° C. After addition the reaction mixture wasstirred at 5° C. for 2 minutes then a solution of hydrocinnamaldehyde(20.0 g, 0.149 mol) in anhydrous tetrahydrofuran (20 ml) was added over1 minute. After 15 minutes at 5° C. the cooling bath was removed and thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was quenched with water (200 ml), then extracted withethyl acetate (3×100 ml). The combined extracts were washed withsaturated sodium chloride solution (200 ml), dried (potassium carbonate)then evaporated to give an orange oil which was purified by distillationunder vacuum. (±)-(3,4-Epoxybutyl)-benzene was obtained as a colourlessoil (5.2 g, 23%), bp 80°-85° C. (4 mbar).

Step B: 2(RS)-(2-Phenylethyl)morpholine

The title compound was obtained (2.55 g, 38%) from(±)-(3,4-epoxybutyl)-benzene (5.15 g, 0.0348 mol) and 2-aminoethylhydrogen sulphate (20.63 g, 0.146 mol) as described in Example 2, Step AMS, CI⁺, m/z=192 for (M+H)⁺. ¹ H NMR (360 MHz, CDCl₃) δ1.63-1.85 (2H,m), 2.53-2.91 (6H, m), 3.38-3.42 (1H, m), 3.58 (1H, ddd, J₁ =3, J₂ =J₃=11 Hz), 3.88 (1H, dd, J₁ =2, J₂ =11 Hz), 7.15-7.29 (5H, m).

Step C: 3-((2(RS)-(2-Phenylethyl)morpholin-4-yl)methyl)-indole HydrogenOxalate

The title compound free base was obtained (0.94 g) from3-(Dimethylaminomethyl)indole and 2(RS)-(2-phenylethyl)morpholine asdescribed in Example 2, Step B. The hydrogen oxalate salt had mp170°-171° C. (ethanol). ¹ H NMR (360 MHz, DMDO-d₆) δ1.64-1.70 (2H, m),2.44-2.69 (4H, m), 3.05-3.16 (2H, m), 3.53-3.60 (2H, m), 3.92 (1H, d,J=12 Hz), 4.14 (2H, s), 7.02-7.28 (7H, m), 7.39-7.42 (2H, m), 7.70 (1H,d, J=8 Hz), 11.29 (1H, s). Found: C, 68.04; H, 6.44; N, 6.98. C₂₁ H₂₄ N₂O.0.9C₂ H₂ O₄ requires C, 68.21; H, 6.48; N, 6.98%.

EXAMPLE 43-((2(RS)-(Phenoxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

38% Aqueous formaldehyde (0.9 ml) was added dropwise to a stirredsolution of 2(RS)-(phenoxymethyl)morpholine (2.10 g, 0.0109 mmol) inglacial acetic acid (8 ml) and water (4 ml). After stirring for 10minutes this solution was treated with 1H-pyrrolo[2,3-b]pyridine (1.18g, 0.010 mmol). The reaction mixture was stirred at room temperature for20 hours. The mixture was poured onto 2M sodium hydroxide solution (180ml) and extracted with ethyl acetate (3×80 ml). The combined extractswere washed with saturated sodium chloride solution (80 ml), dried(sodium sulphate) then evaporated to give a gum which was purified bycolumn chromatography on silica (300 g) using ethyl acetate/methanol(20:1) to afford the title compound free base (2.30 g, 65%) as a gum.The hydrogen oxalate salt had mp 188°-189° C. (ethanol) MS, CI⁺, m/z=324for (M+H)⁺. ¹ H NMR (360 MHz, DMSO-d₆) δ2.55-2.75 (2H, m), 3.14 and 3.30(each 2H, each 2H, each d, J=12 Hz), 3.86-4.03 (4H, m), 4.08-4.20 (3H,m), 6.84-7.27 (6H, m), 7.46 (1H, s), 8.07 (1H, dd, J₁ =1, J₂ =8 Hz),8.27 (1H, dd, J₁ =1, J₂ =5 Hz), 11.43 (1H, s). Found: C, 60.61; H, 5.43;N, 9.97. C₁₉ H₂₁ N₃ O2.C₂ H₂ O₄ requires C, 61.01; H, 5.61; N, 10.16%.

EXAMPLE 53-((2(RS)-(2-Phenylethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

Step A: 3-Dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine

A mixture of 1H-pyrrolo[2,3-b]pyridine (18.07 g, 0.153 mol),dimethylamine hydrochloride (13.11 g, 0.161 mol) and paraformaldehyde(4.92 g, 0.164 mol) in n-butanol (500 ml) was heated at reflux for 35minutes. The mixture was allowed to cool overnight and the precipitatedsolid collected by filtration. The filtrate was evaporated and theresidue triturated with ethyl acetate to afford a second solid. Thesolids were combined, suspended in saturated aqueous potassium carbonatesolution (500 ml) and extracted with dichloromethane (twice). Thecombined extracts were washed with saturated potassium carbonate (250ml) then saturated sodium chloride solution (500 ml), dried (magnesiumsulphate) then evaporated to a small volume, with the productcrystallising out of solution during evaporation. Diethyl ether wasadded and the title compound collected as a solid (18.13 g, 67%). ¹ HNMR (360 MHz, DMSO-d₆) δ2.19 (6H, s), 3.61 (2H, s), 7.03 (1H, dd, J₁ =5,J₂ =8 Hz), 7.36 (1H, d, J=2 Hz), 8.00 (1H, dd, J₁ =2, J₂ ==8 Hz), 8.20(1H, dd, J₁ =2, J₂ =5 Hz), 11.47 (1H, broad s).

Step B:3-((2(RS)-(2-Phenylethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

3-Dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 2.28 mmol) and2(RS)-(2-phenylethyl)morpholine (437 mg, 2.28 mmol) were heated atreflux in toluene (20 ml), with stirring, for 20 hours. The reactionmixture was cooled, treated with silica (200 mg) and activated charcoal(200 mg), filtered, then evaporated to dryness to give the titlecompound free base as a colourless gum (570 mg, 78%). The hydrogenoxalate salt had mp 200°-201° C. (ethanol/water). MS, CI⁺, m/z 322 for(M+H)⁺. ¹ H NMR (360 MHz, DMSO-d₆) δ1.64-1.71 (2H, m), 2.47-2.70 (4H,m), 3.02-3.14 (2H, m), 3.43-3.59 (2H, m), 3.93 (1H, d, J=10 Hz), 4.13(2H, s), 7.10-7.28 (6H, m), 7.55 (1H, s), 8.12 (1H, d, J=7 Hz), 8.25(1H, dd, J₁ =1, J₂ =5 Hz), 11.83 (1H, s). Found: C, 64.07; H, 5.98; N,10.02. C₂₀ H₂₃ N₃ O.C₂ H₂ O₄ requires C, 64.22; H, 6.12; N, 10.21%.

EXAMPLE 6 2-((2(RS)-(Phenoxymethyl)morpholin-4-yl)methyl)benzimidazole

2-(Chloromethyl)benzimidazole (172 mg, 1.03 mmol) and2(RS)-(phenoxymethyl)morpholine (200 mg) were heated in ethanol (8 ml)at 80° C. (oil bath temperature) in the presence of potassium carbonate(142 mg, 1.03 mmol) for 2 hours. The mixture was cooled then evaporatedto dryness. The residue was partitioned between water (10 ml) and ethylacetate (25 ml). The organic layer was separated and the aqueousre-extracted with ethyl acetate (25 ml). The combined organics weredried (sodium sulphate) then evaporated to give a beige gum which waspurified by column chromatography on silica (150 g) using ethyl acetateto ethyl acetate/methanol (25:1) to afford the title compound as a paleyellow solid (220 mg, 66%). mp 171°-172° C. (ethyl acetate/n-hexane).MS, CI⁺, mz=324 for (M+H)⁺. ¹ H NMR (360 MHz, CDCl₃) δ2.40 (1H, dd, J₁=J₂ =10 Hz), 2.51 (1H, ddd, J₁ =3, J₂ =J₃ =10 Hz), 2.79 (1H, d, J=10Hz), 2.99 (1H, d, J=10 Hz), 3.82 (1H, ddd, J₁ =3, J₂ =J₃ =10 Hz),3.91-4.06 (6H, m), 6.88 (2H, dd, J₁ =1, J₂ =8 Hz), 6.95 (1H, ddd, J₁ =1,J₂ =J₃ =8 Hz), 7.24-7.29 (4H, m), 7.57-7.61 (2H, m). Found: C, 70.55; H,6.51; N, 12.96. C₁₉ H₂₁ N₃ O₂ requires C, 70.57; H, 6.55; N, 12.99%.

EXAMPLE 7 2-((2(RS)-(2-Phenylethyl)morpholin-4-yl)methyl)benzimidazoleHydrogen Oxalate

The title compound free base was obtained (220 mg, 52%) from2-(chloromethyl)benzimidazole, 2(RS)-(2-phenylethyl)morpholine andpotassium carbonate as described in Example 6. The hydrogen oxalate salthad mp 197°-198° C. (ethanol/water) MS, CI⁺, m/z=322 for (M+H)⁺. ¹ H NMR(360 MHz, DMSO-d₆) δ1.62-1.70 (2H, m), 2.07 (1H, dd, J₁ =J₂ =11 Hz),2.32 (1H, ddd, J₁ =3, J₂ =J₃ =11 Hz), 2.55-2.69 (2H, m), 2.77 (1H, d, J=11 Hz), 2.84 (1H, d, J =11 Hz), 3.41-3.45 (1H, m), 3.55 (1H, dd, J₁ =J₂=11 Hz), 3.81-3.85 (3H, m), 7.13-7.27 (7H, m), 7.51-7.54 (2H, m). Found:C, 60.24; H, 5.40; N, 9.03. C₂₀ H₂₃ N₃ O.1.5C₂ H₂ O₄ requires C, 60.52;H, 5.74; N, 9.21%.

EXAMPLE 83-((2(RS)-(4-Chlorophenoxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

Step A: 2(RS)-(4-Chlorophenoxymethyl)morpholine

The title compound was obtained (10.8 g, 36%) from(±)-4-chlorophenyl-2,3-epoxypropyl ether and 2-aminoethyl hydrogensulphate as described in Example 2, Step A. mp 51°-52° C. MS, CI⁺,m/z=228 for (M+H)⁺. ¹ H NMR (360 MHz, CDCl₃) δ2.71-3.04 (4H, m), 3.67(1H, ddd, J₁ =3, J₂ =J₃ =11 Hz), 3.82-3.98 (4H, m), 6.84 (2H, d, J=8Hz), 7.21 (2H, d, J=8 Hz). Found: C, 57.92; H, 5.94; N, 5.92. C₁₁ H₁₄ClNO₂ requires C, 58.03; H, 6.20; N, 6.15%.

Step B:3-((2(RS)-(4-Chlorophenoxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo-[2,3-b]pyridineHydrogen Oxalate

2(RS)-(4-Chlorophenoxymethyl)morpholine (650 mg, 2.85 mmol) and3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.85 mmol) wereheated at reflux in toluene (20 ml), with stirring, for 18 hours. Thereaction mixture was cooled, treated with silica (200 mg) and activatedcharcoal (200 mg), filtered, then evaporated to give the title compoundfree base as a flaky solid (870 mg, 85%), mp 140°-141° C. The hydrogenoxalate salt had mp 190°-191° C. (ethanol/water) MS, CI⁺, m/z=358 for(M+H)⁺. ¹ H NMR (360 MHz, DMSO-d₆) δ2.50-2.68 (2H, m), 3.04 (1H, d, J=12Hz), 3.18 (1H, d, J=12 Hz), 3.64 (1H, dd, J₁ =J₂ =12 Hz), 3.90-4.02 (4H,m), 4.11 (2H, s), 6.94 (2H, d, J=9 Hz), 7.11 (1H, dd, J₁ =4, J₂ =8 Hz),7.31 (2H, d, J=9 Hz), 7.54 (1H, s), 8.12 (1H, dd, J₁ =1, J₂ =8 Hz), 8.24(1H, dd, J₁ =1, J₂ =4 Hz), ].1.76 (1H, s). Found: C, 56.57; H, 4.77; N,9.18. C₁₉ H₂₀ ClN₃ O₂.C₂ H₂ O₄ requires C, 56.32; H, 4.95; N, 9.38%.

EXAMPLE 92-((2(RS)-(4-Chlorophenoxymethyl)morpholin-4-yl)methylbenzimidazole

The title compound was obtained (300 mg, 56%) from2(RS)-(4-Chlorophenoxymethyl)morpholine and2-(chloromethyl)benzimidazole as described in Example 6. mp 163°-164° C.(ethyl acetate/n-hexane). Found: C, 64.04; H, 5.54; N, 11.55. C₁₉ H₂₀ClN₃ O₂ requires C, 63.77; H, 5.63; N, 11.74%.

EXAMPLE 10 3-((2(RS)-(Phenoxymethyl)morpholin-4-yl)methyl)-quinolineHydrogen Oxalate

Quinoline-3-carboxaldehyde (447 mg, 2.8 mmol),2(RS)-(phenoxymethyl)morpholine (500 mg, 2.59 mmol) and anhydrous formicacid (0.1 ml) were heated at 120° C. (oil bath temperature), withstirring, for 6 hours. The reaction mixture was cooled, 2M hydrochloricacid (20 ml) added and the solution washed with ethyl acetate (20 ml).The aqueous was basified to pH=11 with 2M aqueous sodium hydroxide, thenextracted with ethyl acetate (2×30 ml). The combined organics were dried(sodium sulphate) then evaporated to give a gum which was purified bycolumn chromatography on silica (200 g) using ethyl acetate to ethylacetate/methanol (25:1) to afford the title compound free base as a paleyellow gum (340 mg, 36%). The hydrogen oxalate salt had mp 164°-166° C.(ethanol/water). MS CI⁺, m/z=335 for (M+H)⁺. ¹ H NMR (360 MHz, DMSO-d₆)δ2.23 (1H, dd, J₁ =J₂ ==11 Hz), 2.35 (1H, ddd, J₁ =3, J₂ =J₃ =11 Hz),2.80 (1H, d, J=11 Hz), 2.97 (1H, d, J=11 Hz), 3.61 (1H, ddd, J₁ =2, J₂=J₃ =11 Hz), 3.80-3.92 (4H, m), 3.96 (2H, d, J=5 Hz), 6.89-6.94 (3H, m),7.23-7.28 (2H, m), 7.59-7.64 (1H, m), 7.73-7.78 (1H, m), 7.97-8.04 (2H,m), 8.29 (1H, d, J=2 Hz), 8.90 (1H, d, J=2 Hz). Found: C, 63.38; H,5.84; N, 6.48. C₂₁ H₂₂ N₂ O₂.C₂ H₂ O₄.0.5H₂ O requires C, 63.73; H,5.81; N, 6.46%.

EXAMPLE 113-((2(S)-(Phenylmethlyloxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

Step A: (+)-2(S)-(Phenylmethyloxymethyl)morpholine

The title compound was obtained (2.33 g, 23%) from 2-aminoethyl hydrogensulphate and (-)-2(benzyloxymethyl)oxirane as described in Example 2,Step A. ¹ H NMR (360 MHz, CDCl₃) δ2.65 (1H, dd, J₁ =10, J₂ =12 Hz),2.78-2.93 (3H, m), 3.41 (1H, dd, J₁ =5, J₂ =10 Hz), 3.48 (1H, dd, J₁ =5,J₂ =10 Hz), 3.58-3.68 (2H, m), 3.89 (1H, d, J=10 Hz), 4.54 (1H, d, J=12Hz), 4.56 (1H, d, J=12 Hz), 7.25-7.34 (5H, m), [α]²⁷° C._(D) +2.4°(c=1.0, methanol), MS, CI⁺, m/z=208 for (M+H)⁺.

Step B:3-((2(S)-(Phenylmethyloxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

The title compound free base was obtained (670 mg, 87%) from(+)-2(S)-(phenylmethyloxymethyl)morpholine and3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine as described in Example8, Step B. The hydrogen oxalate salt had mp 160°-161° C. (ethanol/water)MS, CI⁺, m/z=338 for (M+H)⁺. ¹ H NMR (360 MHz, DMSO-d₆) δ2.58 (1H, dd,J₁ =J₂ =11 Hz), 2.72 (1H, dd, J₁ =J₂ =11 Hz), 3.10 (1H, d, J=11 Hz),3.19 (1H, d, J=11 Hz), 3.43 (1H, dd, J₁ =4, J₂ =10 Hz), 3.48 (1H, dd, J₁=4, J₂ =10 Hz), 3.63 (1H, dd, J₁ =J₂ =11 Hz), 3.75-3.78 (1H, m), 3.92(1H, d, J=11 Hz), 4.21 (2H, s), 4.45 (2H, s), 7.13 (1H, dd, J₁ =4.5, J₂=8 Hz), 7.24-7.36 (5H, m), 7.57 (1H, s), 8.16 (1H, dd, J₁ =1, J₂ =8 Hz),8.26 (1H, dd, J₁ =1, J₂ =4.5 Hz), 11.84 (1H, s). [α]²⁶° C._(D) =-14.0°(c=0.5, methanol/water (14:1)). Found: C, 59.39; H, 5.46; N, 9.23.C₂₀H₂₃ N₃ O₂.1.3C₂ H₂ O₄ requires C, 59.73; H, 5.68; N, 9.25%.

EXAMPLE 123-((2(R)-(Phenylmethyloxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

Step A: (-)-2(R)-(Phenylmethyloxymethyl)morpholine

The title compound was obtained (2.85 g, 32%) from 2-aminomethylhydrogen sulphate and (+)-2(benzyloxymethyl)oxirane as described inExample 2, Step A. MS, CI⁺, m/z=208 for (M+H)⁺. [α]²⁷° C._(D) =-2.0°(c=1.0, methanol).

Step B:3-((2(R)-(Phenylmethyloxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

The title compound free base was obtained (620 mg, 81%) from(-)-2(R)-(phenylmethyloxymethyl)morpholine and3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine as described in Example8, Step B. The hydrogen oxalate salt had mp 160°-161° C. (ethanol/water)MS, CI⁺, m/z=338 for (M+H)⁺. [α]²⁶° C._(D) +136° (c=0.5, methanol/water(14:1). Found: C, 60.04; H, 5.67; N, 9.26.C₂₀ H₂₃ N₃ O₂.1.2C₂ H₂ O₄requires C, 60.40; H, 5.75; N, 9 43%.

EXAMPLE 133-((2(RS)-(4-Methoxyphenoxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

Step A: 2(RS)-(4-Methoxyphenoxymethyl)morpholine

The title compound was obtained (10.66 g, 35%) from(±)-2,3-epoxypropyl-4-methoxyphenyl ether and 2-aminoethyl hydrogensulphate as described in Example 2, Step A. mp 34°-35° C. MS, CI⁺,m/z=224 for (M+H)⁺, ¹ H NMR (360 MHz, CDCl₃) δ2.71-3.10 (4H, m), 3.67(1H, ddd, J₁ =3, J₂ =J₃ =11 Hz), 3.76 (3H, s), 3.80-4.00 (4H, m), 6.81(2H, d, J=7 Hz), 6.85 (2H, d, J=7 Hz). Found: C, 62.24; H, 7.61; N,6.23.C₁₂ H₁₇ NO₃.0.5H₂ O requires C, 62.05; H, 7.81; N, 6.03%.

Step B:((2(RS)-(4-Methoxyphenoxymethyl)morpholin-4-yl)methyl-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

The title compound free base was obtained (710 mg, 70%) from2(RS)-(4-methoxyphenoxy)methyl)morpholine and3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine as described in Example8, Step B. The hydrogen oxalate salt had mp 183°-184° C.(ethanol/water). MS, CI⁺, m/z=354 for (M+H)⁺. ¹ H NMR (360 MHz, DMSO-d₆)δ2.49-2.75 (2H, m), 3.05 (1H, d, J=12 Hz), 3.21 (1H, d, J=12 Hz), 3.64(1H, dd J₁ =J₂ =12 Hz), 3.69 (3H, s), 3.85-4.00 (4H, m), 4.13 (2H, s),6.84 (4H, s), 7.11 (1H, dd, J₁ =5, J₂ =8 Hz), 7.55 (1H, s), 8.13 (1H,dd, J₁ =1, J₂ =8 Hz), 8.24 (1H, dd, J₁ =1, J₂ =5 Hz), 11.79 (1H, s).Found: C, 59.42; H, 5.69; N, 9.23.C₂₀ H₂₃ N₃ O₃.C₂₀ H₂₃ O₄ requires C,59.59; H, 5.68; N, 9.47%.

EXAMPLE 14((2(RS)-(3-Chlorophenoxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

Step A: 2(RS)-(3-Chlorophenoxymethyl)morpholine

The title compound was obtained (9.8 g, 32%) as a gum from(±)-3-chlorophenyl-2,3-epoxypropyl ether and 2-aminoethyl hydrogensulphate as described in Example 2, Step A. MS, CI⁺, m/z=228 for (M+H)⁺.¹ H NMR (360 MHz, CDCl₃) δ2.72-3.05 (4H, m), 3.68 (1H, ddd, J₁ =3, J₂=J₃ =11 Hz), 3.82-4.00 (4H, m), 6.78-6.82 (1H, m), 6.90-6.95 (2H, m),7.18 (1H, dd, J₁ =J₂ =8 Hz). Found: C, 57.53; H, 6.21; N, 5.75. C₁₁ H₁₄ClNO₂ requires C, 58.03; H, 6.20; N, 6.15%.

Step B:((2(RS)-(3-Chlorophenoxymethyl)morpholin-4-yl)methyl)-1H-pyrrolo[2,3-b]pyridineHydrogen Oxalate

The title compound free base was obtained (660 mg, 80%) from2(RS)-(3-chlorophenoxymethyl)morpholine and3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine as described in Example8, Step B. The hydrogen oxalate salt had mp 177°-178° C.(ethanol/water). ¹ H NMR (360 MHz, DMSO-d₆) δ2.50-2.68 (2H, m), 3.06(1H, d, J=12 Hz), 3.20 (1H, d, J=12 Hz), 3.66 (1H, dd, J₁ =J₂ =12 Hz),3.92-4.07 (4H, m), 4.13 (2H, s), 6.88-6.92 (1H, m), 6.98-7.02 (2H, m),7.11 (1H, dd, J₁ =4, J₂ =8 Hz), 7.29 (1H, dd, J₁ =J₂ =8 Hz), 7.56 (1H,s), 8.13 (1H, d, J=8 Hz), 8.25 (1H, dd, J₁ =1, J₂ =4 Hz), 11.80 (1H, s).Found: C, 55.58; H, 5.21; N, 8.92. C₁₉ H₂₀ ClNO₃ O₂.C₂ H₂ O₄.0.25H₂ Orequires C, 55.76; H, 5.01; N, 9.29%.

We claim:
 1. A compound of formula I, or a salt thereof or a prodrugthereof: ##STR8## wherein Y represents an optionally substitutedbicyclic heteroaromatic ring system containing one or two nitrogenatoms, the ring system comprising a six-membered aromatic orheteroaromatic ring fused to a five- or six-membered heteroaromaticring; andZ represents an optionally substituted aryl(C₁₋₆)alkyl,aryloxymethyl or aryl(C₁₋₆)alkoxymethyl group.
 2. A compound as claimedin claim 1 wherein Y represents an optionally substituted 2- or3-indolyl, 2- or 3-quinolyl, 3-indazolyl, 2-benzimidazolyl, or 2- or3-pyrrolo[2,3-b]pyridyl ring system.
 3. A compound as claimed in claim 1represented by formula IIA, and salts and prodrugs thereof: ##STR9##wherein n is zero, 1 or 2;one of V and X is CH or nitrogen and the otheris CH; W represents a chemical bond or an oxygen atom; R¹ representshydrogen or C₁₋₆ alkyl; and R² and R³ independently represent hydrogen,halogen, trifluoromethyl, cyano, nitro, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl(C₁₋₆)alkoxy or C₂₋₆alkylcarbonyl.
 4. A compound as claimed in claim 1 represented byformula IIB, and salts and prodrugs thereof: ##STR10## wherein n iszero, 1 or 2;W represents a chemical bond or an oxygen atom; R¹represents hydrogen or C₁₋₆ alkyl; and R² and R³ independently representhydrogen, halogen, trifluoromethyl, cyano, nitro, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkyl, C₁₋₆ alkoxy, aryl (C₁₋₆)alkoxy, aryl(C₁₋₆) alkoxy or C₂₋₆ alkylcarbonyl; and U representsnitrogen or CH.
 5. A compound as claimed in claim 1 represented byformula IIC, and salts and prodrugs thereof: ##STR11## wherein n iszero, 1 or 2;W represents a chemical bond or an oxygen atom; and R² andR³ independently represent hydrogen, halogen, trifluoromethyl, cyano,nitro, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₁₋₆ alkyl, C₁₋₆alkoxy, aryl (C₁₋₆) alkoxy, or C₂₋₆ alkylcarbonyl.
 6. A compound asclaimed in claim 1 selected from:3-(2-benzylmorpholin-4-ylmethyl)indole;3-(2-phenoxymethylmorpholin-4-ylmethyl)indole;3-[2-(2-phenylethyl)morpholin-4-ylmethyl]indole;3-(2-phenoxymethylmorpholin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine;3-[2-(2-phenylethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;2-(2-phenoxymethylmorpholin-4-ylmethyl)benzimidazole;2-[2-(2-phenylethyl)morpholin-4-ylmethyl)benzimidazole;3-[2-(4-chlorophenoxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;2-[2-(4-chlorophenoxymethyl)morpholin-4-ylmethyl]benzimidazole;3-(2-phenoxymethylmorpholin-4-ylmethyl)quinoline;3-[2(S)-(benzyloxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;3-[2(R)-(benzyloxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;3-[2-(4-methoxyphenoxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;3-[2-(3-chlorophenoxymethyl)morpholin-4-ylmethyl]-1H-pyrrolo[2,3-b]pyridine;and salts and prodrugs thereof.
 7. A pharmaceuticalcomposition comprising a compound as claimed in in claim 1 inassociation with a pharmaceutically acceptable carrier.
 8. A process forthe preparation of a compound as claimed in claim 1 which comprises:(A)reacting a compound of formula III with a compound of formula IV:##STR12## wherein Y and Z are as defined in claim 1, and L represents asuitable leaving group; or (B) for the preparation of a compound offormula I wherein Y represents an optionally substituted indol-3-yl,indazol-3-yl or 4-, 5-, 6- or 7-azaindol-3-yl moiety:reacting a compoundof formula IV as defined above with a compound of formula V:

    Y.sup.1 --H                                                (V)

wherein Y¹ represents an optionally substituted indol-3-yl, indazol-3-ylor 4-, 5-, 6- or 7-azaindol-3-yl moiety; in the presence of asubstantially equimolar amount of formaldehyde; or (C) for thepreparation of a compound of formula I wherein Y represents anoptionally substituted 3-quinolyl moiety:reacting a compound of formulaIV as defined above with a compound of formula VI:

    Y.sup.2 --CHO                                              (VI)

wherein Y² represents an optionally substituted 3-quinolyl moiety; inthe presence of anhydrous formic acid; and (D) subsequently, whererequired, converting a compound of formula I initially obtained into afurther compound of formula I by conventional methods.
 9. A method forthe treatment and/or prevention of disorders of the dopamine system,which method comprises administering to a patient in need of suchtreatment an effective amount of a compound as claimed in claim 1.